Les scientifiques découvrent un moyen précédemment inconnu par lequel les cellules décomposent les protéines.

24 août 2023

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Des protéines à durée de vie courte contrôlent l'expression des gènes dans les cellules afin d'accomplir un certain nombre de tâches vitales, de l'aide à la formation de connexions dans le cerveau à l'aide à la défense immunitaire du corps. Ces protéines sont fabriquées dans le noyau et sont rapidement détruites une fois leur travail terminé.

With the aid of a machine learning tool called AlphaFold that predicts protein structures, plus results from a series of lab experiments, the team was able to flesh out the details of the mechanism. They established that midnolin has a 'Catch domain'—a region of the protein that grabs other proteins and feeds them directly into the proteasome, where they are broken down. This Catch domain is composed of two separate regions linked by amino acids (think mittens on a string) that grab a relatively unstructured region of a protein, thus allowing midnolin to capture many different types of proteins.

Of note are proteins like Fos that are responsible for turning on genes that prompt neurons in the brain to wire and rewire themselves in response to stimuli. Other proteins like IRF4 activate genes that support the immune system by ensuring that cells can make functional B and T cells.

'The most exciting aspect of this study is that we now understand a new general, ubiquitination-independent mechanism that degrades proteins,' Elledge said.

In the short term, the researchers want to delve deeper into the mechanism they discovered. They are planning structural studies to better understand the fine-scale details of how midnolin captures and degrades proteins. They are also making mice that lack midnolin to understand the protein's role in different cells and stages of development.

The scientists say their finding has tantalizing translational potential. It may offer a pathway that researchers can harness to control levels of transcription factors, thus modulating gene expression, and in turn, associated processes in the body.

'Protein degradation is a critical process and its deregulation underlies many disorders and diseases,' including certain neurological and psychiatric conditions, as well as some cancers, Greenberg said.

For example, when cells have too much or too little of transcription factors such as Fos, problems with learning and memory may arise. In multiple myeloma, cancer cells become addicted to the immune protein IRF4, so its presence can fuel the disease. The researchers are especially interested in identifying diseases that may be good candidates for the development of therapies that work through the midnolin-proteasome pathway.

'One of the areas we are actively exploring is how to tune the specificity of the mechanism so it can specifically degrade proteins of interest,' Gu said.

Journal information: Science

Provided by Harvard Medical School